Synthesis, antidepressant evaluation and QSAR studies of novel 2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)-N-(substituted phenyl)acetamides

Article abstract of DOI:10.1016/j.bmcl.2010.05.100

In search for novel antidepressants, a series of 2-(5H-[1,2,4]triazino[5,6- b]indol-3-ylthio)-N-(substituted phenyl)acetamides was synthesized and screened for potential antidepressant activity by tail suspension test (TST) in mice. Number of synthesized compounds exhibited impressive antidepressant activity, measured in terms of percentage decrease in immobility duration (%DID). QSAR analysis was also undertaken which correlated three parameters FOSA, PISA, and glob with biological activity.

Full text of DOI:10.1016/j.bmcl.2010.05.100

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4661–4664
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, antidepressant evaluation and QSAR studies of novel
2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)-N-(substituted phenyl)acetamides
*
Suhas M. Shelke, Sharad H. Bhosale
Department of Pharmaceutical Chemistry, Bharati Vidyapeeth University, Poona College of Pharmacy, Pune 411 038, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In search for novel antidepressants, a series of 2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)-N-(substituted
phenyl)acetamides was synthesized and screened for potential antidepressant activity by tail suspension
test (TST) in mice. Number of synthesized compounds exhibited impressive antidepressant activity, mea-
sured in terms of percentage decrease in immobility duration (%DID). QSAR analysis was also undertaken
which correlated three parameters FOSA, PISA, and glob with biological activity.
Received 10 March 2010
Revised 10 May 2010
Accepted 27 May 2010
Available online 1 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
5H-[1,2,4]triazino[5,6-b]indole
Antidepressant
Tail suspension test
QSAR
Major depressive disorder (MDD) is highly rampant psycholog-
ical illness with 9–18% prevalence and ranking fourth among the
causes of death or injury worldwide.1,2 Monoamine hypothesis of
depression, the most widely accepted one, emphasizes the dys-
function of the norepinephrine (NE), serotonin (5-HT), and dopa-
mine (DA) neurotransmitters in the corticolimbic synaptic cleft
as responsible for depression.3 Although clinically used antidepres-
sants have varying mechanism of actions; they all however eventu-
ally increase brain monoamine levels. Clinical limitations and
adverse effects of currently used antidepressants necessitate con-
tinuous development of novel, efficient and safe drugs for treat-
ment of depression.4 Additional reason for encouraging research
in this field comes from the prediction that by 2020 MDD is ex-
pected to be the second leading cause of disease or injury
worldwide.5
clic phenylacetamides.14–18 Herein we report synthesis, antide-
pressant evaluation and QSAR studies of title compounds (3a–3r).
Substituted acetamides were prepared as per routine18 proce-
dure which involves reaction of primary amines with chloroacetyl
chloride in glacial acetic acid containing saturated solution of so-
dium acetate. The tricyclic compound 1,2,4-triazino[5,6-b]indole-
3-thione 2 was prepared referring to a previously reported meth-
od.7 Isatin 1 was condensed with thiosemicarbazide by refluxing
in aqueous solution of potassium carbonate. The solution so
formed was filtered and acidified with glacial acetic acid to yield
condensed product 2. Synthesis of title compounds 3a–3r was
accomplished by stirring overnight solution of 2 in dry dimethyl
sulfoxide (DMSO) containing anhydrous milled potassium carbon-
ate with appropriate acetamides (Scheme 1).19 Yields of final
compounds were in the range of 66–78% after recrystallization
Derivatives of 1,2,4-triazino[5,6-b]indole-3-thione are known to
possess diverse biological activities like actoprotector,6 antiviral,7
antihypoxic, anti-inflammatory,8 antimalarial,9 antimicrobial,10
antitumor,11 and hepatoprotective.12 Importantly, this tricyclic
structure is comparable to b-carboline (9H-pyrido[3,4-b]indole),
an endogenous monoamine oxidase (MAO) inhibitor.13 So we con-
ceived it interesting to evaluate derivatives of 1,2,4-triazino[5,6-
b]indole-3-thione for antidepressant activity. In an attempt to
explore novel antidepressant compounds, we designed the present
series of 2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)-N-(substituted
phenyl)acetamides. While designing present series, cognizance
was taken of central nervous system activity of various heterocy-
O
N
a
NH
S
O
N
H
N
N
H
1
2
b
H
N
N
N
R
S
N
O
N
H
3a-3r
* Corresponding author. Tel.: +91 9011032735; fax: +91 20 25439383.
E-mail address: dr_shbhosale@rediffmail.com (S.H. Bhosale).
Scheme 1. Reagents and conditions: (a) NH2C(S)NHNH2, K2CO3, H2O, reflux, 4 h; (b)
RNHCOCH2Cl, K2CO3, DMSO, rt, 16 h. (For R, refer Table 1.)
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.05.100

4662
S. M. Shelke, S. H. Bhosale / Bioorg. Med. Chem. Lett. 20 (2010) 4661–4664
from N,N-dimethylformamide–water. Structure conformation of
synthesized compounds was done by IR, 1H NMR, 13C NMR, 13C
DEPT, MS, and elemental analysis.
of 6 min.21 In this established behavioral model, ability of a com-
pound to decrease immobility duration is taken as a measure of
its antidepressant activity. Solutions of the synthesized com-
pounds as well as of standard drugs (moclobemide, fluoxetine,
and imipramine) were prepared in DMSO and administered intra-
peritoneally (ip) to mice. To control group, DMSO was injected ip at
a constant volume of 5 mL/kg. Synthesized compounds (30 mg/kg;
ip) were administered thrice in 24 h duration (sub-chronic) at t = 0,
18, and 24 h. Similar dosing regimen was followed for standard
drugs. Test was performed 1 h after the administration of last dose.
Percentage decrease in immobility duration (%DID) for test and
standard drugs was calculated using following formula:
IR spectrum of prototype compound 3l showed prominent
absorption bands of N–H stretching in secondary amides near
3289 cmꢀ1 and an amide carbonyl at 1660 cmꢀ1. Presence of aro-
matic skeleton is confirmed by peak at 3050 cmꢀ1 corresponding
to aromatic C–H stretching. 1H NMR of 3l displayed singlets at d
2.24 for methyl protons and d 4.25 for methylene protons alpha
to carbonyl group. Multiplets at d 7.1–8.28 affirmed the presence
of eight aromatic protons. Further, a broad singlet at d 10.28 re-
vealed the presence of –NH– proton. 13C NMR of 3l indicated pres-
ence of methyl carbon with peak at d 20.67, methylene carbon with
a peak at d 35.58 and carbonyl carbon with a peak at 166.73. Peaks
for fifteen carbons in the aromatic region d 112.99–166.02 under-
lined the presence of required aromatic skeleton. Mass spectra
(ESI) of 3l showed a molecular ion peak at m/z 372.1 (M+Na+).19
For the purpose of biological evaluation of synthesized com-
pounds, adult male Swiss Albino mice (22 2 g) were used. Ani-
mals were maintained in humidity and temperature controlled
rooms with day–night cycle. They were allowed to acclimatize
with the environment for one week before commencement of the
experiments. Free access to food and water was permitted. Title
compounds were screened for antidepressant activity employing
tail suspension test (TST).20 In TST, after initial escape-oriented
movements, mice develop an immobile posture when placed in
an inescapable stressful situation. This stressful situation involved
haemodynamic stress of being hung in an uncontrollable fashion
by their tail. Duration of immobility was measured for a period
%DID ¼ ½ðA ꢀ BÞ=Aꢁ ꢂ 100;
where A is the duration of immobility (s) in control group and B is
the duration of immobility (s) in test group.
Majority of the synthesized compounds exhibited considerable
antidepressant potential as evident from their high %DID values
(Table 1). Any substituent on the phenyl ring diminished the activ-
ity of parent compound 3a from small to considerable extent
depending upon its type and position. By and large for all the sub-
stituents, biological activity increased as we went from ortho- to
para-position. Presence of bulky non-polar groups on phenyl ring
as in 3b and 3c tended to lessen the activity drastically. Com-
pounds with polar substituents like 3d, 3j, and 3p were all effective
in appreciably reducing immobility duration though not better
than their un-substituted counterpart 3a. Replacement of phenyl
by benzyl as in 3q shrunk the activity to some extent. Again,
decline in activity was noted on replacing phenyl by cyclohexyl
Table 1
Antidepressant evaluation of synthesized compounds with observed and predicted values of log (%DID) for training and test set compounds
H
N
N
N
R
S
N
O
N
H
Compounda
R
TST
log (%DID)
Pre.
Duration of immobility (s)
(mean SEM)b
% Decrease in immobility
duration (%DID)
Expt.
Res.
Training set
3a
3b
3d
3e
3f
3g
3h
3i
3k
3m
3n
3o
3q
Phenyl
51.5 7.1
138.7 10.1c
84.3 5.4
100.2 7.2
100.5 13.7
129.2 8.5
120.8 11.7
75.1 6.1
70.62
20.87
51.89
42.84
42.66
26.29
31.08
57.15
58.75
20.82
68.33
67.59
56.75
1.849
1.320
1.715
1.632
1.630
1.420
1.492
1.757
1.769
1.318
1.835
1.830
1.754
1.829
1.309
1.667
1.674
1.712
1.453
1.397
1.773
1.784
1.381
1.773
1.793
1.777
0.020
0.011
0.048
2-Methylphenyl
2-Chlorophenyl
2-Bromophenyl
2-Nitrophenyl
3-Methylphenyl
3-Methoxyphenyl
3-Chlorophenyl
3-Nitrophenyl
4-Methoxyphenyl
4-Chlorophenyl
4-Bromophenyl
Benzyl
ꢀ0.042
ꢀ0.082
ꢀ0.033
0.095
ꢀ0.016
ꢀ0.014
ꢀ0.063
0.062
72.3 6.0
138.8 8.1c
55.5 7.7
56.8 12.1
75.8 4.7
0.037
ꢀ0.023
Test set
3c
3j
3l
2-Methoxyphenyl
3-Bromophenyl
4-Methylphenyl
4-Nitrophenyl
Cyclohexyl
132.7 9.2
58.6 4.1
121.7 10.2
66 7.6
92.0 11.41
55.8 9.6
69.1 8.4
53.5 4.3
175.3 8.5
24.30
66.57
30.57
62.35
47.51
68.16
60.58
69.48
—
1.386
1.823
1.485
1.795
—
—
—
—
—
1.435
1.793
1.446
1.782
—
—
—
—
—
ꢀ0.049
0.030
0.040
0.013
—
—
—
—
—
3p
3rd
Moclobemide
Imipramine
Fluoxetine
Control
n = 6.
Data were analyzed by one way ANOVA followed by Dunnett’s test.
a
Dose: 30 mg/kg.
p < 0.01 versus control except 3b and 3m.
p < 0.05 versus control.
Detected as an outlier in QSAR analysis by MLR.
b
c
d

S. M. Shelke, S. H. Bhosale / Bioorg. Med. Chem. Lett. 20 (2010) 4661–4664
4663
Table 2
Descriptors used in final MLR analysis
Descriptor Description25
Dipole
SASA
FOSA
FISA
Computed dipole moment of the molecule
Total solvent accessible surface area in square angstroms using a probe with a 1.4 Å radius
Hydrophobic component of the solvent accessible surface area (SASA) (saturated carbon and attached hydrogen)
Hydrophilic component of the SASA (SASA on N, O, and H on heteroatoms)
PISA
p
(carbon and attached hydrogen) component of the SASA
WPSA
glob
Weakly polar component of the SASA (halogens, P, and S)
Globularity descriptor, (4
molecule
p
r2)/(SASA) where r is the radius of a sphere with a volume equal to the molecular volume. Globularity is 1.0 for a spherical
Volume
dip2/V
QP log BB
IP
Total solvent accessible volume in cubic angstroms using a probe with a 1.4 Å radius
Square of the dipole moment divided by the molecular volume
Predicted brain/blood partition coefficient
PM3 calculated ionization potential
EA
PM3 calculated electron affinity
as in 3r. In TST, many of the synthesized compounds like 3a, 3n, 3o,
3j, and 3p exhibited activity very comparable to standard antide-
pressant drugs moclobemide, imipramine and fluoxetine.
and biological activity, compounds were divided into training set
of thirteen compounds and test set of four compounds. Best QSAR
model was selected on the basis of statistical parameters like
squared correlation coefficient (R2), standard deviation (SD), Fish-
er’s value (F) and T-value. Generated model was cross validated
by computing q2 ðRc2vÞ with ‘Leave one out’ (LOO) process and test
set prediction. The final statistically valid QSAR model with three
descriptors is given in Table 3. From this model it can be seen that
two parameters, that is, FOSA and glob negatively correlate with
log (%DID), whereas PISA correlates positively. Correlation matrix
of independent variables involved in the model is given in Table 4.
Experimental, predicted and residual values of log (%DID) for train-
ing and test set compounds are enumerated in Table 1. The graph
of predicted log (%DID) versus experimental is depicted in Figure 1.
Plot of residual log (%DID) against experimental is shown in
Figure 2.
Descriptor FOSA is described as the hydrophobic component of
the solvent accessible surface area (SASA). It represents aliphatic
part of exposed hydrophobic surface area due to saturated carbon
and attached hydrogen. As FOSA is negatively correlated with
log (%DID), any aliphatic substituent in the molecule which in-
creases FOSA, will decrease biological activity. This explains the re-
duced biological activity of compounds like 3b or 3c with methyl
or methoxy substituents, respectively. Descriptor PISA quantifies
The quantitative structure–activity relationship (QSAR) analysis
was undertaken to establish the relationship between antidepres-
sant activity of the synthesized and their molecular descriptors. For
the purpose of QSAR, log (%DID) was taken as an activity parame-
ter. Structures were built and cleaned-up (Universal Force Field)
in Maestro.22 Next, the structures were processed using Ligprep23
and minimized using MacroModel24 with OPLS_2005 force field.
The OPLS (Optimized Potentials for Liquid Simulations) force field
was initially developed by Jorgensen.25 OPLS force fields are re-
puted for successful computation of liquid state thermodynamic
properties26 and protein/protein–ligand modeling.27 OPLS_2005
is an enhanced version of this force field developed by Schrödinger
to provide a larger coverage of organic functionality. In OPLS_2005
all torsional parameters have been refit to reproduce the confor-
mational energetics derived at a higher level of quantum theory
and additional charges have been fit to support additional organic
functionality.24
Molecular descriptors were calculated for minimized structures
using Qikprop.28 Qikprop predicts several physically significant
descriptors and pharmaceutically relevant properties of organic
molecules. The QSAR model was generated by multiple linear
regression (MLR) analysis using Strike29 as a statistical package.
For final statistical analysis, a set of 12 descriptors was selected
on the basis of correlation matrix, descriptor significance, and
training set size. Brief description of these descriptors is given in
Table 2. During initial runs, 3r was detected as an outlier and
was thus excluded from the final run. Based on structural variation
the
p component of SASA, that is, it reflects hydrophobicity of
the molecule due to aromatic region. As PISA is positively corre-
lated with log (%DID), any substitution which decreases aromatic
hydrophobic makeup of the molecule will shrink its activity. This
fact is corroborated by diminished activity of 3a on substitution,
as any substitution on phenyl ring of 3a leads to decrease in PISA.
Table 3
Best QSAR model generated by MLRa
1.85
1.75
1.65
Variable
Coefficient
Standard error ( )
T-value
Intercept
FOSA
PISA
1.0134 ꢃ 101
ꢀ3.6655 ꢃ 10ꢀ3
3.3460 ꢃ 10ꢀ3
ꢀ1.1865 ꢃ 101
2.0727
4.8893
8.3505
3.3454
4.4567
4.3895 ꢃ 10ꢀ4
1.0002 ꢃ 10ꢀ3
2.6622
glob
1.55
a
Statistical values: N = 13, SD = 0.0593,
R
2 = 0.9287, F(3.0, 9.0) = 39.1,
R2 = 0.9287
P = 1.735 ꢃ 10ꢀ5, q2 = 0.8713, RMS = 0.0668.
1.45
Training set
Test set
1.35
1.25
Table 4
Correlation matrix for independent variables involved in MLR equation
FOSA
1.0000
PISA
glob
1.25
1.35
1.45
1.55
1.65
1.75
1.85
Experimental log (% DID)
FOSA
PISA
glob
ꢀ0.3138
1.0000
0.2512
Figure 1. Plot of predicted log (%DID) against experimental log (%DID) for training
and test set compounds.
ꢀ0.0762
1.0000

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S. M. Shelke, S. H. Bhosale / Bioorg. Med. Chem. Lett. 20 (2010) 4661–4664
0.200
0.150
tary data associated with this article can be found, in the online
version, at doi:10.1016/j.bmcl.2010.05.100.
0.100
0.050
0.000
-0.050
-0.100
-0.150
-0.200
References and notes
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1.318
1.386
1.485
1.630
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19. General procedure for synthesis of 2-(5H-[1,2,4]triazino[5,6-b]indol-3-ylthio)-
N-substituted acetamides 3a–3r: To a solution of 2 (0.005 mol) in dry DMSO
(25 mL) containing anhydrous milled potassium carbonate (0.01 mol),
appropriate 2-chloro-N-substituted acetamide (0.005 mol) was added.
Reaction mixture was kept for stirring 16 h at room temperature. Reaction
mixture was then poured into water with stirring. The precipitated product
was filtered, washed with water, dried, and recrystallised from DMF–water to
yield 3a–3r.
1.715
1.757
1.795
1.830
1.849
Experimental log (% DID)
Figure 2. Plot of residual log (%DID) against experimental log (%DID).
glob is globularity descriptor, (4p
r2)/(SASA), where r is the radius
of a sphere with a volume equal to the molecular volume. Thus,
glob can be looked at as a measure of bulkiness. Since glob inver-
sely correlates with log (%DID), any substituent which adds to glob
will lessen the activity of the compound. This justifies decreased
activity of compounds with bulky substituents.
To conclude, the present work revealed the synthesis of 2-(5H-
[1,2,4]triazino[5,6-b]indol-3-ylthio)-N-(substituted phenyl)aceta-
mides. Many of the synthesized compounds significantly reduced
immobility duration in TST which was comparable to standard
drugs, underlying their antidepressant potential. QSAR studies of
synthesized compounds indicated that increased aliphatic charac-
ter and bulkiness decreased biological activity, whereas increased
aromatic character enhanced biological activity. Information pre-
sented here may effectively be used for designing newer molecules
with improved antidepressant potential.
Physicochemical data for 3l: Yield 78%; mp 273–278 °C; IR (KBr,
m
cmꢀ1): 3289,
3122, 3050, 2983, 1660, 1535. 1H NMR (DMSO-d6, d): 2.24 (s, 3H, –CH3), 4.25 (s,
2H, –CH2–), 7.10 (d, 2H, Ar-H), 7.42 (t, 1H, Ar-H), 7.49 (d, 2H, Ar-H), 7.58 (d, 1H,
Ar-H), 7.68 (t, 1H, Ar-H), 8.30 (d, 1H, Ar-H), 10.28 (br s, 1H, –NH–). 13C NMR
(DMSO-d6, d): 20.67, 35.58, 112.99, 117.81, 119.43 (2C), 121.73, 122.75, 129.39
(2C), 131.20, 132.61, 136.73, 140.69, 141.44, 146.79, 166.02, 166.73. 13C DEPT
(DMSO-d6, d): Positive peaks: 20.67, 112.98, 119.39 (2C), 121.74, 122.76,
129.39 (2C), 131.20; Inverse peaks: 35.57. MS (ESI) m/z: 372.1(M+Na+, 100%).
Elemental analysis C18H15N5OS Calcd. (Found): C, 61.87 (62.09); H, 4.33 (4.17);
N, 20.04 (20.33), S, 9.18 (9.02).
Acknowledgments
One of the author (S.M.S.) is indebted to Council of Scientific
and Industrial Research (CSIR), New Delhi for awarding Senior Re-
search Fellowship. Authors are thankful to Dr. K. R. Mahadik, Prin-
cipal, Poona College of Pharmacy, for providing research facilities.
Authors are also grateful to Dr. R. A. Joshi and Dr. (Mrs.) R. R. Joshi,
National Chemical Laboratory (NCL), Pune for their help. Assistance
of Indian Institute of Technology-Bombay, Mumbai in carrying out
spectral analysis is also acknowledged.
20. Stéru, L.; Chermat, R.; Thierry, B.; Simon, P. Psychopharmacology 1985, 85, 367.
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2007, 15, 2907.
22. Maestro, version 9.0, Schrödinger, LLC, New York, NY, 2009.
23. LigPrep, version 2.3, Schrödinger, LLC, New York, NY, 2009.
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29. Strike, version 1.8, Schrödinger, LLC, New York, NY, 2009.
Supplementary data
Various descriptors used in QSAR analysis and physicochemical
details of the synthesized compounds are mentioned. Supplemen-